Articles

Weight Gain in Bipolar Disorder:
Causes and Treatments

Dr. Printz is assistant clinical professor, Dr. Stricks is research scientist, and Dr. Malaspina is professor of psychiatry, all in the Department of Psychiatry at Columbia University in New York City.
Dr. Clark is a psychiatric resident at St. Luke’s/Roosevelt Medical Center in New York City.

Disclosure: Dr. Printz receives research support from GlaxoSmithKline and Pfizer, and is on the speaker’s bureau for AstraZeneca, GlaxoSmithKline, Ortho-McNeil and Pfizer. Dr. Malaspina is a consultant to Bristol-Myers Squibb and Janssen, and is on the speaker’s bureau for Wyeth.

Focus Points

• Bipolar disorder patients are significantly more likely to be overweight or obese, thus placing them at an increased risk for obesity-related conditions, such as diabetes and hypertension.

• Weight gain may be caused by mood stabilizers and/or bipolar disorder-related symptoms, such as increased appetite and decreased activity during depression.

• In helping patients evaluate the relative risks and benefits of treatments, clinicians should consider the medical background of the patient, the liability of the medication to promote weight gain, and the ability of the patient to actively participate in pharmacologic and nonpharmacologic weight-reduction strategies.

Abstract

Bipolar disorder is associated with a high incidence of significant obesity, much of which is likely iatrogenic and caused by mood-stabilizing medications. This obesity produces a significant psychosocial burden, increases the risk for a range of comorbid medical disorders, and leads to higher rates of medication noncompliance and clinical relapse. Fortunately, the range of mood-stabilizing agents is expanding and several of the newer agents have a lower tendency to promote weight gain. Also, a greater focus on medication-associated weight gain has increased the data available to aid in medication selection. This article summarizes epidemiologic data relating obesity to bipolar illness, describe the associations between specific mood stabilizers and weight gain, and provide practical approaches to the management of weight gain in bipolar patients.

Introduction

Despite increasing awareness of the harmful effects of obesity, rates of obesity1 continue to climb in developed nations.2 The Third National Health and Nutrition Examination Survey found that the rates of being overweight or obese (body mass index [BMI] ≥25 [Table 1]) were 63% for males and 55% for females. Data derived from the survey3 demonstrated that type 2 diabetes, gallbladder disease, coronary heart disease, hypercholesterolemia, and hypertension all occurred at significantly higher rates in the overweight and obese subgroups of the population. It is important to remember that even the relatively modest excess weight found in the overweight group increased risk for these medical comorbidities. With the exception of hypercholesterolemia, progressively higher rates were seen with increasing obesity class. Indeed, obesity in the United States is credited with approximately 280,000 excess deaths per year.4

It is clearly incumbent upon clinicians to minimize the potential for iatrogenic weight gain induced by medications. This is particularly true for psychiatrists managing chronic psychotic and affective disorders, where symptoms of the illness (altered appetite, poor impulse control, decreased rates of exercise) may conspire with the effects of medications to produce tremendous weight gain in some patients. Since many psychiatric patients are less likely to adhere to regular medical evaluation by an internist, psychiatrists need to be aware of the causes and consequences of weight gain, monitor weight and metabolic parameters, pursue primary prevention of obesity when possible, and be aware of treatment options for obesity.

This review seeks to provide clinically useful information for the practicing psychiatrist by summarizing the literature relating bipolar disorder and obesity, comparing the weight gains associated with different mood stabilizers, and providing options for the treatment of obesity in bipolar patients.

Weight Gain Associated With Bipolar Disorder

Recent studies suggest that obesity occurs at higher rates in patients with bipolar disorder. Elmslie and colleagues5 compared bipolar patients to controls from a population database and found higher rates of being overweight in female patients relative to controls (44% versus 25%) and higher rates of obesity in female (20% versus 13%) and male (19% versus 10%) patients relative to controls. An elevated waist-to-hip ratio (indicative of central obesity and increased cardiovascular risk) was more common in patients relative to controls for both women (59% versus 17%) and men (58% versus 35%). Fagiolini and colleagues6 found that 68% of bipolar subjects were either overweight (36%) or obese (32%) and that BMI correlated with number of previous depressive episodes. McElroy and colleagues7 reviewed the data on 644 patients with bipolar disorder treated in a naturalistic fashion. They found that being overweight, obese, or extremely obese occurred in 58%, 21%, and 5% of the sample, respectively. Comorbid medical conditions that occurred at higher rates in the overweight or obese bipolar patients included hypertension, diabetes, and arthritis. Degree of exposure to psychotropic medications known to cause weight gain correlated positively with current BMI, while frequency of exercise correlated negatively. These data highlight the elevated rates of obesity and associated medical consequences in bipolar patients.

Mood Stabilizers and Weight Gain

Medications which are considered mood stabilizing in nature include lithium, a subset of antiepileptic drugs (AEDs), and the range of atypical antipsychotic medications. Not surprisingly, most of the data relating weight gain to AEDs and antipsychotics have been collected in patients with epilepsy and schizophrenia, respectively.

Lithium

Lithium use has long been associated with weight gain. In their review of 12 early lithium studies in bipolar patients, Goodwin and Jamison8 reported that weight gain was a subjective complaint of approximately one in five patients. Weight gain was also cited as the second most important cause of medication noncompliance, which can in turn produce relapse.9 Many other studies have reported similar weight gain in bipolar patients treated with lithium.10-16 The reported average increases in body weight range from 4 kg11 to 6.3 kg,13 with the largest increases occurring in the first 2 years of treatment.11 In direct comparisons, average weight gain in patients treated with lithium is similar to those treated with valproate.13,15 In summary, recent data support earlier observations that lithium causes moderate weight gain in a substantial fraction of patients and marked weight gain in a smaller percentage.

Antiepileptic Drugs

Valproate

Weight gain is a side effect commonly associated with valproate use. Dinesen and colleagues17 observed that 57% of 63 epilepsy patients treated with valproate gained more than 4 kg during treatment. In a study of 100 children with epilepsy treated with valproate,18 44% developed significant weight gain. Corman and colleagues19 retrospectively characterized the weight gain in 70 epilepsy patients treated with valproate for 27 months and found that 71% had gained at least 5% of baseline weight, compared to 43% of patients in a smaller carbamazepine control group. A 4 kg weight gain was seen in 70% of the valproate patients in that study. In a cross-sectional study of women with epilepsy treated with valproate or carbamazepine monotherapy for at least 2 years,20 mean BMI was significantly higher with valproate (24.4) than carbamazepine (22.9). Higher postprandial insulin levels were also observed in the valproate-treated patients, providing evidence of possible insulin resistance.

A similar association was found in studies by Isojarvi and colleagues,21 who observed higher rates of obesity (defined by BMI≥25) in a group of women with epilepsy naturalistically treated with valproate (59%) relative to those treated with carbamazepine (28%) or to controls (12%). In the subset of valproate patients who gained weight, the average weight gain was 21 kg. The valproate-treated group also had higher rates of insulin resistance, menstrual dysfunction, elevated androgen levels, and polycystic ovaries.22

A subset of these obese valproate-treated women were subsequently switched to lamotrigine and experienced significant weight loss, with resolution of associated endocrine and metabolic abnormalities. In a recent study, Pylvanen and colleagues23 compared valproate-treated epilepsy patients with controls matched by BMI. Obesity was present in 49% of subjects in both groups and leptin values were comparable. However, insulin levels were higher in both normal weight and obese valproate subjects relative to controls. Isojarvi and colleagues21 proposed that valproate-induced weight gain led to insulin resistance and hyperinsulinemia and thereby to increased androgen levels and polycystic ovaries. The finding by Pylvanen and colleagues23 provides further evidence of valproate-associated weight gain and its potential association to other medical problems.

There are relatively little data relating valproate to weight gain in bipolar patients. Valproate has been compared to olanzapine in two multicenter acute mania studies. In a 3-week double-blind, randomized monotherapy study,24 the mean increases in weight in the olanzapine and valproate groups were 2.5 and 0.9 kg, respectively. Weight gain was reported as an adverse event by 12% and 7.9% of subjects in the olanzapine and valproate groups, respectively. In a 12-week acute mania trial, Zajecka and colleagues25 reported significantly greater weight gain in an olanzapine group (4.0 kg) compared to a valproate group (2.5 kg). In that study, weight gain was identified as an adverse event in 25% of olanzapine patients and 10% of valproate patients. Body weight appeared to plateau at approximately 28 days for valproate and 42 days for olanzapine. Taken together, these studies suggest that valproate produces significant weight gain in a minority of bipolar patients, but that it produces less weight gain than olanzapine.

Carbamazepine

Carbamazepine has demonstrated efficacy in acute mania and maintenance treatment of bipolar disorder. Similar to valproate, carbamazepine is more effective for periods of mood elevation than depression. As noted in a series of studies comparing carbamazepine to lithium16 or valproate,20,21 weight gain is less severe with carbamazepine than with either of lithium or valproate.

Lamotrigine

Lamotrigine has demonstrated efficacy for bipolar depression and rapid-cycling bipolar disorder. Devinsky and colleagues26 evaluated the weight change in 463 subjects drawn from adjunctive lamotrigine epilepsy trials and found a median weight gain of only 0.1 kg after a mean duration of treatment for 318 days. In a 32-week double-blind, randomized trial of lamotrigine and valproate monotherapy in patients with epilepsy (n=133), Biton and colleagues27 reported that valproate produced a mean weight gain of 12.8 lbs, which had not yet reached a plateau at the end of the study. In contrast, weight gain in the lamotrigine group averaged only 1.3 lbs. In a randomized, double-blind comparison of lamotrigine and valproate for adolescents with epilepsy,28 lamotrigine produced no weight gain while valproate treatment resulted in significant weight gain by week 10, with a further increase over the subsequent 22 weeks.

The bipolar literature supports the minimal weight effect observed in the epilepsy literature. For example, in a 26-week, double-blind monotherapy maintenance study in rapid-cycling patients, Calabrese and colleagues29 observed a 1.1 kg weight gain in lamotrigine patients relative to a loss of 0.3 kg in placebo-treated patients. In contrast, in the lithium versus lamotrigine bipolar maintenance study previously cited,14 11% of lamotrigine-treated subjects gained 7% of body weight over 18 months. The reason for this discrepant finding is unclear. However, the literature suggests that there is minimal weight gain associated with lamotrigine.

Topiramate

Topiramate is a structurally novel AED approved in 1996 for the treatment of epilepsy. Although topiramate failed to separate from placebo in multicenter monotherapy trials for acute mania, several studies suggest antimanic efficacy when the drug is used as an adjunctive treatment.30-32

Appetite suppression and weight loss have been observed in trials using topiramate for both epilepsy and bipolar disorder. A mean loss of 9% of body weight was observed in a naturalistic study of epilepsy patients maintained on topiramate for an average of 2 years.33 In a prospective study, weight loss was evaluated in a sample of epilepsy patients taking adjunctive topiramate for at least 1 year. Significantly more weight was lost in the obese (BMI ≥30) subset of subjects relative to the entire sample at both 3 months (4.2 versus 3.0 kg) and 12 months (10.9 versus 5.9 kg) of treatment. Weight loss at 3 months correlated with reduced caloric intake, suggesting a direct effect of topiramate on appetite.

In a retrospective review34 of naturalistic treatment of bipolar patients, adjunctive use of topiramate was associated with weight loss in half of the patients. The mean weight change was 14.2 lbs and the mean dose of topiramate was higher in patients who lost weight (138 mg/day) than in those who did not lose weight (70 mg/day). In another adjunctive study in mania, weight loss was approximately 9.4 lbs over 5 weeks.31 In a comparison of topiramate and bupropion augmentation for bipolar depression, weight loss over 8 weeks was 5.8 kg and 1.2 kg, respectively.35 Marcotte36reviewed the data from 298 outpatients with bipolar disorder or cyclothymia treated openly with topiramate for up to 4 years. Overall, the mean weight loss was 12.5 lbs. Greater weight loss was associated with a longer duration of treatment; for patients treated <6 months, 6–12 months, and >12 months, the weight loss was 8.0, 13.8, and 17.3 lbs, respectively. Greater weight loss was also observed with higher doses of topiramate; mean dose was 212 mg/day for patients losing <20 lbs and 282 mg/day for those losing >20 lbs. Lastly, McElroy and colleagues37 conducted a 14-week, double blind, placebo-controlled trial of topiramate (mean dose 212 mg/day) in obese patients with binge-eating disorder. They observed a greater reduction in the topiramate group in binge frequency, binge-eating obsessions, BMI, and body weight. Mean weight loss was almost 6 kg in the topiramate group and 1 kg in the placebo group.

The potential benefits of topiramate for either mood stabilization or weight reduction must be balanced against the potential for troublesome side effects. For topiramate, side effects most often include parasthesias, somnolence, and cognitive difficulties (including memory, concentration, and word-finding difficulties). To some degree, these side effects can be reduced with more gradual titration of the medication.

In summary, weight loss has been associated with topiramate treatment in patients with a variety of disorders when used as either a monotherapy or an adjunctive treatment. The degree of weight loss appears dose dependent, is positively related to baseline weight, and is maintained or improved beyond at least 1 year of treatment.

Antipsychotic Medications

The association between early atypical antipsychotics and weight gain in patients with schizophrenia is well known. This extensive literature has been widely reviewed,38-40 and our discussion will therefore be limited to more recent findings. Comparison of weight gain liabilities across the atypical agents is facilitated by a meta-analysis41 of data from 81 published clinical trials. The predicted mean weight gains at 10 weeks of treatment derived from that analysis are listed in Table 2. Unfortunately, there was insufficient quetiapine data to include that medication in the analysis. Although providing important comparison data to assist in medication selection, this meta-analysis only estimates short-term weight gain.

Olanzapine

Multiple studies support the efficacy of olanzapine in the acute and maintenance treatment of bipolar mania. However, olanzapine also produces significant weight gain. In a retrospective chart review42 of 121 schizophrenia patients undergoing naturalistic treatment, olanzapine use was associated with a significantly greater weekly weight increase (0.76 kg/wk) than was seen with typical antipsychotics (0.27 kg/wk), clozapine (0.22 kg/wk), or risperidone (0.15 kg/wk). Other naturalistic data43 from a large sample of schizophrenia patients receiving maintenance antipsychotic monotherapy treatment with haloperidol, olanzapine, or risperidone demonstrated weight gain with each agent of 2.8, 4.6, and 3.1 kg, respectively.

Clinical trials provide more controlled prospective data. In a 3-week, placebo-controlled monotherapy trial for acute mania,44 weight gain was reported in 11.4% of olanzapine patients versus 1.4% of placebo patients. Mean weight change was +1.65 kg for olanzapine and -0.44 kg for placebo. One long-term (mean=6.6 months) prospective open-label extension of an acute mania clinical trial noted a 6.64 kg mean weight gain.45 As mentioned in the above section on valproate, two olanzapine versus valproate acute mania studies also provide evidence for greater weight gain on olanzapine. Of note, the 10-week weight gain with olanzapine (4.0 kg) observed by Zajecka and colleagues25 is nearly identical to that predicted by the meta-analysis of Allison and colleagues.41 This suggests that any effects of diagnosis on weight gain are not as powerful as medication-specific effects. A recent analysis from extended clinical trials46 in schizophrenia suggest that weight gain plateaus by 39 weeks of treatment. With continued treatment of ≤3 years, mean weight gain with olanzapine was 6.3 kg and with haloperidol, the active comparator, it was 0.7 kg.

Clinical treatment would benefit from the ability to predict which patients would gain significant weight with olanzapine. A retrospective analysis47 of weight gain in 1,189 schizophrenia patients treated with olanzapine (mean=13.2 mg) for 1 year divided patients into rapid and non-rapid weight gain groups based upon whether they gained 7% or more of baseline body weight in the first 6 weeks of treatment. Fifteen percent of the sample fell into the rapid weight gain group, whose members gained 2% or more of body weight in the first 2 weeks (4–7 lbs) and who subsequently reached a plateau of approximately 20 lbs gained by 22 weeks. The non-rapid weight gain group, consisting of the other 85% of subjects, gained an average of 4 lbs over the course of the 52-week study. This study suggests that there may be a subgroup of patients at risk for severe weight gain on olanzapine who can be identified based upon rapid weight gain in the first 2 weeks of treatment. Data from olanzapine clinical trials suggests that weight gain is not dosage related.

Clozapine

Clozapine retains an important role as a treatment for severe, refractory mania or rapid cycling but has been associated with weight gain comparable to, or exceeding,48 that of olanzapine. There is also some indication that weight gain with clozapine may not plateau as early as with other atypicals, but may continue over several years of treatment.49 In a recent retrospective 5-year naturalistic study50 of weight gain and diabetes risk in patients with schizophrenia treated with clozapine, it was determined that weight increased by 1.2 lbs/month. The rate of weight gain decreased after 12 months but weight did not plateau until approximately month 46. No correlation between dose and weight gain was observed. The rate of new onset diabetes in this group was remarkably high (37% over 5 years) but did not correlate with weight gain. This finding, also observed in studies of weight gain and diabetes with other atypicals, suggests that different mechanisms are responsible for these two metabolic adverse events.

Risperidone

As estimated by Allison and colleagues,41 mean 10-week weight gain for risperidone is 2.1 kg. Additional data have supported this estimate as well. Wirshing and colleagues48 retrospectively evaluated weight gain in 92 schizophrenia patients and found that risperidone was associated with less weight gain (4.1 kg) than either clozapine (7.5 kg) or olanzapine (8.0 kg). The mean time to maximum weight gain for these three agents were 15.0, 24.9, and 21.2 weeks, respectively. Recently published data from a 1-year double-blind, placebo-controlled schizophrenia trial comparing haloperidol and risperidone51 found a mean weight change in the two groups of -0.73 kg and +2.3 kg. In patients with bipolar disorder, risperidone appears to produce modest weight gain. In a 3-week placebo-controlled multicenter trial of adjunctive risperidone for acute mania,52 weight gain was 1.7 kg for risperidone and 0.5 kg for placebo.

Quetiapine

As recently reviewed by Nasrallah,53 quetiapine is associated with a moderate degree of weight gain (2.08 kg) after 5–6 weeks of treatment, which persists over time (≤12 months) without worsening. This weight change does not appear to be dose related. Based upon this recent data, as well as several studies cited by Allison and colleagues,41 it is reasonable to place quetiapine between risperidone and olanzapine in terms of weight-gain liability.

Ziprasidone

Overall, ziprasidone has been associated with minimal or no weight gain.41,54 No significant weight gain was observed in a short-term placebo-controlled acute mania study54,55 or in schizophrenia trials. In addition, a mean weight loss of 3.6 kg over 6 months of ziprasidone treatment was observed in 40 patients with mental retardation who had previously developed significant weight gain on other agents.56

Aripiprazole

A recent meta-analysis of aripiprazole use in patients with schizophrenia57 (n=1648) revealed a 0.7 kg weight gain over 4–6 weeks (versus 0.6 kg and 1.3 kg for haloperidol and risperidone, respectively). In a 26-week comparison of aripiprazole to olanzapine, weight change was -2.2 kg and +4.4, respectively. Based on this early data, aripiprazole appears to possess no weight-gain liability.

Practical Approach to Weight Gain in the Bipolar Patient

As the data illustrates, significant weight gain is associated with many of the medications we employ for the acute and chronic treatment of bipolar disorder. This data should be used to guide medication selection and factored into the risk:benefit analysis undertaken for any proposed treatment. However, there will be times when medications causing weight gain will need to be used due to a poor response to other medications, the need for polypharmacy, or avoidance of other adverse effects. Prior to instituting treatment, it is helpful to clarify the following issues in order to assist in medication selection:

•Patient’s personal and family liability to obesity and to obesity-related disorders (diabetes, heart disease, dyslipidemia)

After the start of treatment, it is critical to monitor weight change closely, particularly for patients who are not as self-observant. Weight monitoring should become part of the regular routine in patients with chronic illnesses, such as bipolar disorder. Weight monitoring should be incorporated into treatment in a fashion analogous to checking blood levels and monitoring liver function tests and other lab values. For drugs with high weight-gain liability, particularly in patients with other risk factors or higher baseline weight, it makes sense to preempt further weight gain with nutritionist consultation, implementation of an appropriate diet, and a regular exercise program. To minimize frustration in both the patient and clinician, the difficulty of implementing such a program (particularly by someone with a chronic psychiatric illness) should be articulated and understood.

If weight gain occurs during the course of treatment, metabolic and endocrine parameters should be reassessed. Some assessments are medication specific (eg, checking for emergent hypothyroidism with lithium) and some are general (eg, monitoring for elevated fasting blood sugar, checking fasting lipids, following blood pressure more closely). In addition to the non-pharmacologic strategies listed above, a variety of medications can be employed to facilitate weight loss.

Topiramate

Topiramate is an AED with substantial data supporting its efficacy for weight loss. Topiramate appears to be a reasonable choice for a weight-reducing medication for bipolar patients due to its potential antimanic efficacy when used as an augmentation agent, the absence of risk for cycle acceleration, and the low potential for the development of tolerance or abuse. Based upon the data cited, the target dose for optimum weight loss is probably 150–250 mg/day. Introduction at a low dose and gradual titration may reduce side effects.

Sibutramine

Sibutramine is hypothesized to decrease appetite and increase energy expenditure. A recent 48-week placebo-controlled trial was conducted in 1,102 obese adults. Mean weight loss of 4 kg occurred over a 4-week lead-in period, in line with previous short-term clinical trials. Over a subsequent 44-week maintenance period, additional weight loss with continuous or intermittent sibutramine treatment was 3.8 and 3.3 kg, respectively. Weight increased 0.2 kg in the placebo group. This study reaffirmed the efficacy of sibutramine in acute treatment and suggested that benefits are maintained after discontinuation (ie, there was no marked weight gain during placebo group maintenance) and are extended with continued dosing. Potential side effects include dry mouth, constipation, sweating, and headache. Since sibutramine is a potent serotonin and norepinephrine reuptake inhibitor (similar to venlafaxine) it likely has the potential to induce a switch into mania (which has been reported58) or cause cycle acceleration.

Orlistat

Orlistat is a reversible inhibitor of gastric and pancreatic lipases. It acts by blocking the conversion of triglycerides into free fatty acids and monoglycerides, thereby decreasing the rate of absorption of lipids from the intestine. In an 18-month, placebo-controlled trial59 of overweight patients, orlistat produced greater weight loss than placebo (6.5 versus 3.0% at baseline). Although lacking systemic effects, orlistat is associated with gastrointestinal side effects, must be taken three times a day, and requires compliance with a reduced fat diet.

Phentermine

Phentermine is a sympathomimetic drug, with central nervous system actions similar to dextroamphetamine and other stimulants. It is approved only for the short-term treatment of obesity. When combined with fenfluramine, phentermine was associated with increased rates of valvular heart disease and primary pulmonary hypertension, prompting removal from the market of this combination. The risk of cardiopulmonary disease with phentermine monotherapy cannot be entirely ruled out. Most weight loss occurs in the initial treatment period and there is the potential for tolerance or tachyphylaxis.

Although stimulants are frequently used in the treatment of bipolar disorder (particularly bipolar depression with hypersomnia and anergy), the high rates of comorbid substance abuse with the illness mandate careful evaluation of the potential phentermine patient for stimulant abuse liability.

Zonisamide

Weight loss was identified as an adverse event in epilepsy clinical trials of zonisamide, a newer AED. A recent placebo-controlled trial in 60 obese (BMI=36.3) subjects60 documented 5.9 and 0.9 kg weight losses in the zonisamide and placebo groups, respectively. Total weight loss in zonisamide-treated completers was 9.2 kg. This represents promising data, with an effect on weight similar to that of topiramate. However, pending more extensive data, including studies of bipolar patients, it seems prudent to be cautious in its use. Side effects can include sedation, ataxia, dizziness, and difficulty with concentration and memory.

Conclusion

Bipolar disorder is complicated by rates of obesity and related medical conditions which are greater than in the general population. Based upon the studies cited, iatrogenic weight gain due to mood-stabilizing medication is likely responsible for a significant fraction of this added morbidity. There is a pronounced range of weight-gain liability across the spectrum of mood stabilizing agents (Table 3). Lithium, valproate, and olanzapine are associated with the greatest weight gain; carbamazepine, risperidone, and quetiapine with intermediate weight gain; and lamotrigine, ziprasidone, and aripiprazole with no significant weight gain. Topiramate is the only mood stabilizer that produces significant weight loss. It is incumbent upon the clinician to inform and educate the patient about weight gain, monitor weight and related endocrine and metabolic parameters closely, and be aware of pharmacologic and nonpharmacologic strategies to reduce obesity. PP